THE DEVELOPMENT OF CANCER CHEMOTHERAPY AND BASIC CONCEPTS IN CANCER CHEMOTHERAPY

Dr. Twalib A. Ngoma Executive Director - ORCI

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TOPICS TO BE COVERED IN THIS PRESENTATION

Introduction objectives Part 1 Development of cancer chemotherapy Part 2 Basic concepts in cancer chemothewrapy

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OBJECTIVES

To provide knowledge about the most important concepts in cancer chemotherapy To facilitate the transfer of skills in the use of recommended chemotherapeutic regimens and the necessary precautions to be taken To stimulate MMED Clinical Oncology students to acquire deeper and more extensive knowledge of this discipline by further reading of the recommended publications .

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INTRODUCTION

Cancer Chemotherapy is a relatively new treatment modality practiced by medical oncologists.This speciality has emerged in the field of clinical oncology over the last 30 yrs. The broad-based interaction that has developed between the various disciplines involved in the care of the cancer patient through tumour boards and or multidisciplinary clinics, makes the medical oncologist an essential component in the team that makes management decisions and has responsibility for coordinating the selection of appropriate therapy in the event of relapse following primary treatment or where the disease is already disseminated on first presentation.

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TOPICS TO BE COVERED TODAY Historical outline of the development of cancer chemotherapy Cytotoxic drugs in clinical use Procedure for the development, testing and use of chemotherapeutic drugs Basic Concepts in Cancer Chemotherapy

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TOPICS TO BE COVERED -CONT

Classification of cytotoxic drugs according to their effect on the cell cycle Drug resistance Theoretical basis for the effects of Combination Chemotherapy Strategies of combination chemotherapy in solid tumours Problems of schedules in combination chemotherapy 6 MUHAS MMED ONCOLOGY 4/11/2012

HISTORY OF THE DEVELOPMENT OF CANCER CHEMOTHERAPY -1

1946 - 1960 Development of single-drug chemotherapy mainly on a purely empirical basis. Establishment of critical criteria for the clinical development of effective new drugs: criteria of response; toxicity; performance status; optimal tolerated dose. First results from the treatment of leukaemias and malignant lymphomas. Generally poor results in the treatment of advanced solid tumors.
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HISTORY OF DEVELOPMENT OF CANCER CHEMOTHERAPY -2

1960 - 1970 Development of knowledge of cell kinetics and introduction of kinetic concepts into clinical chemotherapy. Broadening of the experimental basis for clinical chemotherapy. Introduction of pharmacokinetic concepts into clinical chemotherapy. First developments in the field of combination chemotherapy Introduction of the concept of the controlled randomized clinical trial into clinical chemotherapy as a basis for continuous progress Further improvement of treatment results in leukaemias and lymphomas and significant progress in the results obtained in the treatment of certain solid tumors.
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HISTORY OF DEVELOPMENT OF CANCER CHEMOTHERAPY -3 1970 to 2000 Development of the concept of the combined modality approach: improved cooperation between the cancer surgeon, radiotherapist and chemotherapist. First positive results in adjuvant chemotherapy.
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HISTORY OF DEVELOPMENT OF CANCER CHEMOTHERAPY - 4

2000 TO DATE Recognition of the late toxicity of chemotherapy and combined radiotherapy and chemotherapy in long-term survivors. Development of new expensive drugs such as Taxanes, Avastin, Herceptin etc Experimental immunotherapy. Development of the concepts of human immunotherapy and first, limited positive results in human immunotherapy.
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PROCEDURES FOR THE DEVELOPMENT TESTING AND USE OF CHEMOTHERAPEUTIC DRUGS

DRUG DEVELOPMENT BY EITHER RANDOM SCREENING OR LOGICAL DESIGN ANIMAL STUDIES TO COLLECT DATA AND FORMULATION PHASE 1 TRIALS TOXICITY - MAXIMUM TOLERATED DOSE PHASE 2 TRIALS EFFICACY IN DIFFERENT TUMOURS PHASE 3 TRIALS COMPARATIVE RANDOMIZED STUDIES IF FOUND TO BE CLINICALLY USEFUL DRUG USE AS ADJUVANT IF CIRCUMSTANCES EXIST OR COMBINE WITH OTHER DRUGS IN ADVANCED DISEASE

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CYTOTOXIC DRUGS IN CLINICAL USE

ALKYLATING AGENTS ANTIMETABOLITES PLANT DERIVED AGENTS-VINCA ALKALOIDS, TAXANES,TOPOISOMERASE INHIBITORS, ETOPOSIDE ANTITUMOUR ANTIBIOTICS MISCELLANEOUS COMPOUNDSangiogenesis & growth factor inhibitors

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BASIC CONCEPTS IN CANCER CHEMOTHERAPY -1 Chemotherapy drugs are developed for their potential to cause a greater proportion of cell death among neoplastic as opposed to normal cells. Neoplastic cells are more susceptible because of their biological and proliferation characteristics

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BASIC CONCEPTS IN CANCER CHEMOTHERAPY -1 Tumour growth Doubling times of tumours increase with tumour mass. As the tumour grows the disease becomes less to cure. The shorter the doubling time at the onset of treatment the better the response to chemotherapy.

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BASIC CONCEPTS IN CANCER CHEMOTHERAPY -2

Mechanism of Action Cytotoxic drugs act against the tumours by interfering with cell division and growth. To understand their mechanism of action and the theories underlying their administration the processes of cell division must be understood 15 MUHAS MMED ONCOLOGY 4/11/2012

Classification of cytotoxic drugs according to their effect on the cell cycle

Predominantly Non Phase Dependent Predominantly Phase Dependent

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Classification of cytotoxic drugs according to their effect on the cell cycle

Predominantly Non Phase Dependent Predominantly Phase Dependent

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Predominantly Non Phase Dependent

Imidazole carbomaxide DTIC Nitrogen Mustard BCNU, CCNU Streptozotocin Doxorubicin, Daunorubicin Cyclophosphamide, Chorambucil Melphalan Mitomycin C, Actinomycin D

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Predominantly Phase Dependent

5FU, METHOTREXATE, 6 MERCAPTOPURINNE CYTOSINE ARABINOSIDE, HYDROXYUREA PROCARBAZINE VINCRISTINE VINBLASTINE ETOPOSIDE

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DIAGRAMMMATIC REPRESENTATION OF THE CELL SPECIFICITY OF CYTOTOXIC DRUGS

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DRUG RESISTANCE

PRIMARY ACQUIRED Selective killing of sensitive cells leaving resistant cells Adaptive change by tumour cells

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ADAPTIVE CHANGE BY TUMOUR CELLS -1

Inhibition of membrane transport A change in the confirmation of an enzyme rendering it insensitive to the drug Deletion of any enzyme necessary to activate the drug Detoxification of the drug to an inactive compound (the normal tissues may also contribute to this) An increase in concentration of a metabolite which can overcome the biochemical lesion produced by the drug tumour population.

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ADAPTIVE CHANGE BY TUMOUR CELLS -2

An increase in concentration of target enzyme A reduced requirement for the metabolite which is a product of the inhibited reaction Development of an alternative pathway which is not inhibited by the drug Change in proliferative characteristics of the tumour population

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EXAMPLES OF DRUG RESISTANCE AND THEIR MECHANISMS OF ACTION -1

Mechanism of resistance

Drug

Insufficient drug uptake by cancer cell ------Methotraxate Insufficient activation of drug -----------------5FU Increased inactivation -------------------6 Mercaptopurine Increased concentration of a target enzyme ---MTX

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EXAMPLES OF DRUG RESISTANCE AND THEIR MECHANISMS OF ACTION - 2

Mechanism of Resistance Drug Decreased requirement for a specific metabolic product --------------------------------L Asparaginase Increased utilization of an alternate biochemical pathway "salvage" ----------------Antimetabolites Rapid repair of a drug induced lesion ------Alkylating agents

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COMBINATION CHEMOTHERAPY
General principles which guide selection of drugs activity against the tumour when used alone Different mechanisms of action Minimal overlapping toxicity Use of optimal dose and schedule 26 MUHAS MMED ONCOLOGY 4/11/2012

THEORETICAL BASIS FOR THE EFFECTS OF COMBINATION CHEMOTHERAPY 1.Cell kinetics factors Drugs with differing toxicities to host tissues and different mechanism of action may, when used in combinations:

Increase tumour cell kill without corresponding increase of host toxicity leading to improved preferential killing

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THEORETICAL BASIS FOR THE EFFECTS OF COMBINATION CHEMOTHERAPY

1.Cell kinetics factors allow for more rapid host recovery and better selectivity leading to more rapid preferential killing kill various segments of neoplastic cell populations

dividing and non dividing cells dividing cells in different phase of the cell cycle leading to more complete remissions and delay of resistant cell populations

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THEORETICAL BASIS FOR THE EFFECTS OF COMBINATION CHEMOTHERAPY

Drugs with additive toxicity to host tissue without addictive tumour cell kill results in decreased effectiveness of combination or even preferential killing of normal host cells.

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STRATEGIES OF COMBINATION CHEMOTHERAPY IN SOLID TUMOURS -1

1. Combining drugs most effective when used singly (a) Simultaneously (b) Sequentially, in sequential combinations.

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STRATEGIES OF COMBINATION CHEMOTHERAPY IN SOLID TUMOURS -2

Administering Courses of non-cycle specific combinations followed by cycle specific combinations - The theoretical basis is that non cycle specific drugs may reduce the high nonproliferating cell pool of solid tumours, increase the proliferating pool and thus render cells more sensitive to cycle specific drugs.

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STRATEGIES OF COMBINATION CHEMOTHERAPY IN SOLID TUMOURS -3

Attempts at synchronisation
Vincristine or hydroxyurea, followed by cyclophosphamide, 5-fluorouracil, methotrexate, cytosine arabinoside or bleomycin. The theoretical basis is that partial and preferential synchronization of normally asynchronous cycling tumour cells renders these, at certain times, more sensitive to cycle-specific drugs. Time schedule is critical to ensure that this occurs preferentially in relation to normal host cells.

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PROBLEMS OF SCHEDULES IN COMBINATION CHEMOTHERAPY -1

1. Choice of drugs used in combinations

Empirical basis: - drugs most effective in a tumour type when used alone no cross resistance, different mechanism of action toxicity spectrum of drugs differing from each other no addictive toxicity leads from animal models : gives little direct information

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PROBLEMS OF SCHEDULES IN COMBINATION CHEMOTHERAPY -2

2. Route of administration: high i.v dose vs daily oral dose, etc. 3. Schedules of administration: pharmacologic and cytokinetic considerations - Intermittent continuous - Simultaneous - sequential - Influence of immunosuppression -host recovery 4: Tumour cell burden: induction maintenance
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PROBLEMS OF SCHEDULES IN COMBINATION CHEMOTHERAPY -3 5: Resistance: previous treatments, killing of various segments of the neoplastic cell population, in order to prevent resistance. 6. Miscellaneous factors: biologic differences of neoplastic cells age and sex of the host 7. Practical considerations: feasibility of experimental designs ambulatory patients distance to treatment centre

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HOMEWORK
THE CELL CYCLE STRUCTURE OF CHROMOSOMES ACQUISITION OF DRUGS-EMPERICAL SCREENING, FORMULATION, TESTING toxicological, pharmacological acceptable one tenth LD10 CLINICAL TESTING PHASE 36 1,2,3 TRIALS MUHAS MMED ONCOLOGY 4/11/2012

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